Advertisement

Hypospadias

Published:September 07, 2021DOI:https://doi.org/10.1016/j.ajog.2021.06.045

      Introduction

      Hypospadias occurs in approximately 0.2 to 4.1 in 1000 live births.
      • Epelboym Y.
      • Estrada C.
      • Estroff J.
      Ultrasound diagnosis of fetal hypospadias: accuracy and outcomes.
      ,
      • Li X.
      • Liu A.
      • Zhang Z.
      • An X.
      • Wang S.
      Prenatal diagnosis of hypospadias with 2-dimensional and 3-dimensional ultrasonography.
      This anomaly of the male genitourinary system occurs when the embryologic urethral folds fail to fuse completely between the 7th and 14th weeks of gestation.
      • Epelboym Y.
      • Estrada C.
      • Estroff J.
      Ultrasound diagnosis of fetal hypospadias: accuracy and outcomes.
      ,
      • Norton M.E.
      Callen’s ultrasonography in obstetrics and gynecology.
      ,
      • Bamberg C.
      • Brauer M.
      • Degenhardt P.
      • Szekessy D.P.
      • Henrich W.
      Prenatal two- and three-dimensional imaging in two cases of severe penoscrotal hypospadias.
      Therefore, the position of the urethral meatus becomes abnormally located along the length of the ventral shaft of the penis, scrotum, or perineum. Chordee (curvature of the penis with ventral shortening) is often present as well.
      • Epelboym Y.
      • Estrada C.
      • Estroff J.
      Ultrasound diagnosis of fetal hypospadias: accuracy and outcomes.
      • Li X.
      • Liu A.
      • Zhang Z.
      • An X.
      • Wang S.
      Prenatal diagnosis of hypospadias with 2-dimensional and 3-dimensional ultrasonography.
      • Norton M.E.
      Callen’s ultrasonography in obstetrics and gynecology.

      Definition

      Hypospadias is diagnosed when the urethral meatal position is abnormally located along the length of the ventral shaft of the penis, scrotum, or perineum.
      • Epelboym Y.
      • Estrada C.
      • Estroff J.
      Ultrasound diagnosis of fetal hypospadias: accuracy and outcomes.
      • Li X.
      • Liu A.
      • Zhang Z.
      • An X.
      • Wang S.
      Prenatal diagnosis of hypospadias with 2-dimensional and 3-dimensional ultrasonography.
      • Norton M.E.
      Callen’s ultrasonography in obstetrics and gynecology.
      ,
      • Odeh M.
      • Ophir E.
      • Bornstein J.
      Hypospadias mimicking female genitalia on early second trimester sonographic examination.
      It has been classified as proximal (urethral meatus between the perineum and midshaft), distal (between the midshaft and the glans of the penis), and glandular (within the glans of the penis).
      • Epelboym Y.
      • Estrada C.
      • Estroff J.
      Ultrasound diagnosis of fetal hypospadias: accuracy and outcomes.
      Alternatively, hypospadias has also been described as anterior (urethral meatus glandular or coronal), middle (penile shaft), and posterior (penoscrotal, scrotal, perineal). Approximately 50% of cases are anterior, 30% are middle, and 20% are posterior.
      • Bamberg C.
      • Brauer M.
      • Degenhardt P.
      • Szekessy D.P.
      • Henrich W.
      Prenatal two- and three-dimensional imaging in two cases of severe penoscrotal hypospadias.

      Ultrasound Findings

      Hypospadias can be diagnosed with ultrasound as a “blunt tip” appearance of the penis on ultrasound, which indicates abnormal tapering of the distal phallus (Figure 1). Ventral shortening and curvature of the penis represents chordee. A “buried” appearance of the penis has been described, in which the penis is significantly foreshortened. The “tulip sign” describes severe hypospadias, in which there is penoscrotal transposition, and the penis is curved and located between the folds of a bifid scrotum. Finally, ventral deflection of the urinary stream in a fan shape has been described; power or color Doppler may be used to illustrate an abnormal origin of the urinary stream.
      • Epelboym Y.
      • Estrada C.
      • Estroff J.
      Ultrasound diagnosis of fetal hypospadias: accuracy and outcomes.
      ,
      • Li X.
      • Liu A.
      • Zhang Z.
      • An X.
      • Wang S.
      Prenatal diagnosis of hypospadias with 2-dimensional and 3-dimensional ultrasonography.
      ,
      • Odeh M.
      • Ophir E.
      • Bornstein J.
      Hypospadias mimicking female genitalia on early second trimester sonographic examination.
      ,
      • Meizner I.
      • Mashiach R.
      • Shalev J.
      • Efrat Z.
      • Feldberg D.
      The “tulip sign”: a sonographic clue for in-utero diagnosis of severe hypospadias.
      Normal amniotic fluid volume is reported in most cases of hypospadias, and polyhydramnios is rarely seen.
      • Epelboym Y.
      • Estrada C.
      • Estroff J.
      Ultrasound diagnosis of fetal hypospadias: accuracy and outcomes.
      The positive predictive value of ultrasound for the prenatal detection of hypospadias has been reported as 72%.
      • Epelboym Y.
      • Estrada C.
      • Estroff J.
      Ultrasound diagnosis of fetal hypospadias: accuracy and outcomes.
      However, as most cases are mild, many cases are not detected at all before birth. Some data have suggested that 3-dimensional ultrasound may give a more precise depiction of the urogenital structures with higher diagnostic yield (Figure 2).
      • Norton M.E.
      Callen’s ultrasonography in obstetrics and gynecology.
      ,
      • Bamberg C.
      • Brauer M.
      • Degenhardt P.
      • Szekessy D.P.
      • Henrich W.
      Prenatal two- and three-dimensional imaging in two cases of severe penoscrotal hypospadias.
      Figure thumbnail gr1
      Figure 1Fetal hypospadias
      Fetal hypospadias demonstrating a small “blunt-ended” penis (arrow) with two echogenic lines at the tip representing prepuce lateral folds.
      Society for Maternal-Fetal Medicine. SMFM Fetal Anomalies Consult Series #4. Am J Obstet Gynecol 2021.
      Figure thumbnail gr2
      Figure 2A 3-dimensional image demonstrating the “tulip sign” in severe hypospadias
      The tulip is formed by a ventrally oriented penis located between two scrotal folds.
      Society for Maternal-Fetal Medicine. SMFM Fetal Anomalies Consult Series #4. Am J Obstet Gynecol 2021.

      Associated Abnormalities

      Although hypospadias is often an isolated finding, it is associated with additional anomalies in 7% to 40% of cases.
      • Epelboym Y.
      • Estrada C.
      • Estroff J.
      Ultrasound diagnosis of fetal hypospadias: accuracy and outcomes.
      ,
      • Norton M.E.
      Callen’s ultrasonography in obstetrics and gynecology.
      ,
      • Odeh M.
      • Ophir E.
      • Bornstein J.
      Hypospadias mimicking female genitalia on early second trimester sonographic examination.
      A variety of genetic, endocrine, and environmental etiologies have been proposed that may increase the risk of hypospadias. A two-hit hypothesis has been suggested, in which an environmental insult combines with an underlying genetic predisposition.
      • Bamberg C.
      • Brauer M.
      • Degenhardt P.
      • Szekessy D.P.
      • Henrich W.
      Prenatal two- and three-dimensional imaging in two cases of severe penoscrotal hypospadias.
      When additional anomalies are present, 40% have been reported to also affect the genitourinary system.
      • Norton M.E.
      Callen’s ultrasonography in obstetrics and gynecology.
      • Bamberg C.
      • Brauer M.
      • Degenhardt P.
      • Szekessy D.P.
      • Henrich W.
      Prenatal two- and three-dimensional imaging in two cases of severe penoscrotal hypospadias.
      • Odeh M.
      • Ophir E.
      • Bornstein J.
      Hypospadias mimicking female genitalia on early second trimester sonographic examination.
      Bifid scrotum has been described in 33% of hypospadias cases, and cryptorchidism in 17%.
      • Epelboym Y.
      • Estrada C.
      • Estroff J.
      Ultrasound diagnosis of fetal hypospadias: accuracy and outcomes.
      Inguinal hernia, vesicoureteral reflux, and ureteropelvic junction obstruction may also be seen.
      • Li X.
      • Liu A.
      • Zhang Z.
      • An X.
      • Wang S.
      Prenatal diagnosis of hypospadias with 2-dimensional and 3-dimensional ultrasonography.
      Less common concurrent genitourinary anomalies include unilateral renal agenesis, bladder exstrophy, and perineal lipoma.
      • Epelboym Y.
      • Estrada C.
      • Estroff J.
      Ultrasound diagnosis of fetal hypospadias: accuracy and outcomes.
      Moreover, hypospadias may be present as part of an underlying genetic syndrome, and additional nongenitourinary anomalies occur in 7% to 10% of cases.
      • Norton M.E.
      Callen’s ultrasonography in obstetrics and gynecology.
      ,
      • Bamberg C.
      • Brauer M.
      • Degenhardt P.
      • Szekessy D.P.
      • Henrich W.
      Prenatal two- and three-dimensional imaging in two cases of severe penoscrotal hypospadias.
      Anomalies of the craniofacial structures as well as the cardiac, pulmonary, gastrointestinal, and central nervous systems have been described in association with hypospadias.
      • Epelboym Y.
      • Estrada C.
      • Estroff J.
      Ultrasound diagnosis of fetal hypospadias: accuracy and outcomes.
      ,
      • Bamberg C.
      • Brauer M.
      • Degenhardt P.
      • Szekessy D.P.
      • Henrich W.
      Prenatal two- and three-dimensional imaging in two cases of severe penoscrotal hypospadias.
      ,
      Online Mendelian Inheritance in Man (OMIM)
      MIM Number: 300633 Hypospadia 1, X-linked; HYSP1.
      Additionally, an increased risk of fetal growth restriction has been reported in cases of hypospadias.
      • Gatti J.M.
      • Kirsch A.J.
      • Troyer W.A.
      • Perez-Brayfield M.R.
      • Smith E.A.
      • Scherz H.C.
      Increased incidence of hypospadias in small-for-gestational age infants in a neonatal intensive-care unit.
      ,
      • Hussain N.
      • Chaghtai A.
      • Herndon C.D.
      • Herson V.C.
      • Rosenkrantz T.S.
      • McKenna P.H.
      Hypospadias and early gestation growth restriction in infants.

      Differential Diagnosis

      The differential diagnosis when hypospadias is seen on prenatal ultrasound includes micropenis, epispadias, and cloacal anomalies.
      • Devesa R.
      • Muñoz A.
      • Torrents M.
      • Comas C.
      • Carrera J.M.
      Prenatal diagnosis of isolated hypospadias.
      In addition, it is important to distinguish between hypospadias and abnormal female genitalia, such as clitoromegaly. One method that has been described to differentiate between male and female genitalia is to measure the angle of the genital tubercle from a horizontal line through the lumbosacral skin surface in the midsagittal plane; if this angle is >30°, the sex is likely to be male.
      • Odeh M.
      • Ophir E.
      • Bornstein J.
      Hypospadias mimicking female genitalia on early second trimester sonographic examination.
      Testicular descent or the “dome sign” of the penis and scrotum also indicate male sex, and parallel lines of the labial folds or visualization of the uterus indicate female sex.
      • Norton M.E.
      Callen’s ultrasonography in obstetrics and gynecology.
      ,
      • Odeh M.
      • Ophir E.
      • Bornstein J.
      Hypospadias mimicking female genitalia on early second trimester sonographic examination.
      Hypospadias is an isolated finding in most cases. Familial inheritance of isolated hypospadias has been documented in an autosomal dominant or X-linked manner in some cases. Recurrence risk may be as high as 14% for a sibling of an affected child, and approximately 4% to 10% of affected boys have an affected father.
      Online Mendelian Inheritance in Man (OMIM)
      MIM Number: 300633 Hypospadia 1, X-linked; HYSP1.
      Hypospadias also can be associated with underlying genetic syndromes, such as Smith-Lemli-Opitz, Wolf-Hirschhorn, multiple lentigines, Opitz G/BBB, Schilbach-Rott, hand-foot-genital, Elsahy-Waters, Pallister-Hall, Bardet-Biedl, Mowat-Wilson, trisomies 13 and 18, triploidy, and many others.
      Online Mendelian Inheritance in Man (OMIM)
      MIM Number: 300633 Hypospadia 1, X-linked; HYSP1.
      ,
      • Devesa R.
      • Muñoz A.
      • Torrents M.
      • Comas C.
      • Carrera J.M.
      Prenatal diagnosis of isolated hypospadias.
      Microdeletion syndromes, such as 19q13.11 and 9p24.3, have been associated with hypospadias. Finally, androgen insensitivity, adrenal hyperplasia, and other endocrine abnormalities have been reported in conjunction with hypospadias, many as part of an underlying syndrome.
      Online Mendelian Inheritance in Man (OMIM)
      MIM Number: 300633 Hypospadia 1, X-linked; HYSP1.

      Genetic Evaluation

      Diagnostic testing (amniocentesis) should be offered when hypospadias is detected, including specifically chromosomal microarray analysis (CMA). If there are additional anomalies, consanguinity, or a family history of a specific condition, gene panel testing or exome sequencing is sometimes useful because CMA does not detect single-gene (Mendelian) disorders. If exome sequencing is pursued, appropriate pretest and posttest genetic counseling by a provider experienced in the complexities of genomic sequencing is recommended. After appropriate counseling, cell-free DNA screening is an option for patients who decline diagnostic evaluation and can be helpful in determining biologic sex with severe hypospadias or ambiguous genitalia.

      Pregnancy and Delivery Management

      Expectant families may be advised that hypospadias is often an isolated finding, but additional anomalies or underlying genetic syndromes are possible. Insufficient evidence exists regarding any potential benefit of antenatal testing, although this is not typically recommended with isolated hypospadias. Timing and mode of delivery should be based on usual obstetrical indications.

      Prognosis

      The most frequent complications of hypospadias are stenosis of the urethral meatus and difficulty controlling the urinary stream.
      • Devesa R.
      • Muñoz A.
      • Torrents M.
      • Comas C.
      • Carrera J.M.
      Prenatal diagnosis of isolated hypospadias.
      Hypospadias is treated with surgery. Prognosis is very favorable among cases of isolated hypospadias. However, outcomes can be more variable in the setting of multiple anomalies or an underlying genetic syndrome.

      Summary

      Hypospadias is an anomaly of the male genitourinary system that results in the abnormal location of the urethral meatus along the length of the ventral shaft of the penis, scrotum, or perineum. Characteristic ultrasound findings, such as “blunt tip,” chordee, or the “tulip sign,” may lead to the diagnosis. A large number of genetic, endocrine, and environmental etiologies have been described in association with hypospadias. Hypospadias is often an isolated finding, although it can be transmitted through families. In addition, it can be associated with additional anomalies in 7% to 40% of cases, most of which affect the genitourinary system but may affect other organ systems as well. Diagnostic testing with amniocentesis should be offered when hypospadias is detected, and standard obstetrical principles should guide timing and mode of delivery. Prognosis is very favorable among isolated cases of hypospadias, although it is more variable in the setting of multiple anomalies or an underlying genetic syndrome.

      References

        • Epelboym Y.
        • Estrada C.
        • Estroff J.
        Ultrasound diagnosis of fetal hypospadias: accuracy and outcomes.
        J Pediatr Urol. 2017; 13: 484.e1-484.e4
        • Li X.
        • Liu A.
        • Zhang Z.
        • An X.
        • Wang S.
        Prenatal diagnosis of hypospadias with 2-dimensional and 3-dimensional ultrasonography.
        Sci Rep. 2019; 9: 8662
        • Norton M.E.
        Callen’s ultrasonography in obstetrics and gynecology.
        6th edition. Elsevier, Amsterdam, the Netherlands2016
        • Bamberg C.
        • Brauer M.
        • Degenhardt P.
        • Szekessy D.P.
        • Henrich W.
        Prenatal two- and three-dimensional imaging in two cases of severe penoscrotal hypospadias.
        J Clin Ultrasound. 2011; 39: 539-543
        • Odeh M.
        • Ophir E.
        • Bornstein J.
        Hypospadias mimicking female genitalia on early second trimester sonographic examination.
        J Clin Ultrasound. 2008; 36: 581-583
        • Meizner I.
        • Mashiach R.
        • Shalev J.
        • Efrat Z.
        • Feldberg D.
        The “tulip sign”: a sonographic clue for in-utero diagnosis of severe hypospadias.
        Ultrasound Obstet Gynecol. 2002; 19: 250-253
        • Online Mendelian Inheritance in Man (OMIM)
        MIM Number: 300633 Hypospadia 1, X-linked; HYSP1.
        Johns Hopkins University, Baltimore, MD2019
        • Gatti J.M.
        • Kirsch A.J.
        • Troyer W.A.
        • Perez-Brayfield M.R.
        • Smith E.A.
        • Scherz H.C.
        Increased incidence of hypospadias in small-for-gestational age infants in a neonatal intensive-care unit.
        BJU Int. 2001; 87: 548-550
        • Hussain N.
        • Chaghtai A.
        • Herndon C.D.
        • Herson V.C.
        • Rosenkrantz T.S.
        • McKenna P.H.
        Hypospadias and early gestation growth restriction in infants.
        Pediatrics. 2002; 109: 473-478
        • Devesa R.
        • Muñoz A.
        • Torrents M.
        • Comas C.
        • Carrera J.M.
        Prenatal diagnosis of isolated hypospadias.
        Prenat Diagn. 1998; 18: 779-788